Fluorine-substituted Analogues Research Articles

Phenotypic analysis of human CYP2C9 polymorphisms using fluorine-substituted tolbutamide.

To investigate the effect of fluorine substitution on tolbutamide (TB) hydroxylation catalyzed by CYP2C9, the hydroxylation of TB and its fluorinated derivative 3'-fluoro-tolbutamide (3'-F-TB) by recombinant human CYP2C9*1, CYP2C9*2, and CYP2C9*3 was analyzed. In general, fluorine substitution near the metabolic site may decrease enzymatic oxidation owing to its electron-withdrawing nature. Fluorine substitution reduced the Michaelis-Menten-derived Km of 4'-hydroxylation of TB catalyzed by CYP2C9*1 from 115 (TB) to 77 (3'-F-TB) µM. In the case of TB hydroxylation catalyzed by CYP2C9*2, the Km value of TB was also reduced by fluorine substitution from 129 to 88 µM. The greatest effect of fluorine substitution on the Km in TB hydroxylation was observed in the catalysis by CYP2C9*3, in which the Km value decreased from 287 to 117 µM. When a mixture containing TB and 3'-F-TB was hydroxylated by CYP2C9, the hydroxylated metabolite ratio in CYP2C9*3 was significantly increased compared with that in CYP2C9*1 and CYP2C9*2 (p < 0.01, Tukey-Kramer test). These results suggest that obtaining the metabolite profiles of fluorine-substituted analogs of the key substrate molecule may be useful as a new tool for phenotyping polymorphic CYP isoforms.

Influence of the Structures of the Carboxylate Porous Coordination Polymers as Stationary Phases for Liquid Chromatography on the Separation Efficiency of the Aniline Derivatives

The possibility of the chromatographic separation of isomeric nitroanilines and fluorine-substituted analogues using porous coordination polymers [Al(OH)(Fum)]n (I) (Fum2– is trans-1,2-ethylenedicarboxylic acid anion), [Al(OH)(Bdc)]n (II) (Bdc2– is 1,4-benzenedicarboxylic acid anion), [Cu3(Btc)2(H2O)3] (III) (Btc3– is 1,3,5-benzenetricarboxylic acid anion), and [Cr3(O)(OH)(H2O)2(Bdc)3] (IV) as stationary phases in a mixture of nonpolar solvents is studied. The separation of the amines is achieved only in the case of [Al(OH)(Fum)]n. Possible relationships of the separation factors of the amines to the sizes of the molecules, polarity, and lipophilicity are examined. Among the factors considered, only the difference between the values of lipophilicity exerts a noticeable effect on the efficiency.

Radiation-Induced Fluorescence from Doped Polyolefins on a Nanosecond Time Scale: Kinetics of the Processes Involving Geminate Radical Ions.

The delayed radiation-induced fluorescence from polyethylene and its alkyl- and fluorine-substituted analogues doped with aromatic luminophores was studied in the time range of 1-1000 ns. Qualitative analysis of the effects of a magnetic field on the fluorescence decay indicated that, in all polyolefins studied, the main portion of the fluorescence observed arose from the recombination of geminate spin-correlated radical ion pairs (RIPs). In the case of polyethylene, this conclusion was supported by observing the effect of an external electric field on the fluorescence decay. It was shown by comparison with the computer simulation of intratrack recombination that the tunneling character of the RIP recombination, which had an asymptotic time dependence of the geminate recombination rate close to t-1, was typical of most studied polyolefins at temperatures below 273 K in the time range studied. The increase to room temperature and above caused a gradual transition to a regime where the geminate recombination rate was mainly determined by the migration of RIP partners with time dependence close to t-3/2. The low estimate of the electron transfer distance upon the ion recombination in this regime was about 2 nm. In polyethylenes, exposed to an irradiation of 0.3-0.4 MGy, the role of charge carrier diffusion became hardly noticeable because of the cross-linking of polyethylene chains and the increase in polymer matrix stiffness. Oxygen, dissolved in a polymer doped with aromatic molecules, caused quenching of the recombination luminescence due to electron transfer from the dopant radical anion to the oxygen molecules. At room temperature, typical distances for such electron transfer were estimated to be ∼1.5 nm.

The chemistry and pharmacology of synthetic cannabinoid SDB-006 and its regioisomeric fluorinated and methoxylated analogs.

Synthetic cannabinoids are the largest and most structurally diverse class of new psychoactive substances, with manufacturers often using isomerism to evade detection and circumvent legal restriction. The regioisomeric methoxy- and fluorine-substituted analogs of SDB-006 (N-benzyl-1-pentyl-1H-indole-3-carboxamide) were synthesized and could not be differentiated by gas chromatography-mass spectrometry (GC-MS), but were distinguishable by liquid chromatography-quadrupole time-of-flight-MS (LC-QTOF-MS). In a fluorescence-based plate reader membrane potential assay, SDB-006 acted as a potent agonist at human cannabinoid receptors (CB1 EC50 = 19nM). All methoxy- and fluorine-substituted analogs showed reduced potency compared to SDB-006, although the 2-fluorinated analog (EC50 = 166nM) was comparable to known synthetic cannabinoid RCS-4 (EC50 = 146nM). Using biotelemetry in rats, SDB-006 and RCS-4 evoked comparable reduction in body temperature (~0.7°C at a dose of 10mg/kg), suggesting lower potency than the recent synthetic cannabinoid AB-CHMINACA (>2°C, 3mg/kg).

Abstract 4791: Targeting ovarian cancer with novel 6-substituted pyrrolo [2,3-d] pyrimidine fluorinated antifolates via cellular uptake by folate receptor á and the proton-coupled folate transporter

Abstract The proton coupled folate transporter (PCFT) is a proton-folate symporter with an acidic pH optimum, while folate receptor (FR) á delivers folate substrates into the cell via endocytosis. FRá and PCFT are highly expressed in ovarian cancer. PCFT transport is favored by acidic pH, including pHs associated with the acidic tumor microenvironment. We previously synthesized a novel class of 6-substituted pyrrolo[2,3-d]pyrimidine thiophene antifolates with 4- and 3-carbon bridge lengths, designated AGF117 and AGF150, targeted to FRá and PCFT, but not the ubiquitously expressed reduced folate carrier (RFC). To increase antitumor specificity and activity, reflecting multi-polar interactions with cellular targets, we synthesized fluorinated analogs of AGF117 and AGF150, designated AGF278 and AGF283. In the presence of a physiologic concentration of reduced folate, AGF278 and AGF283 potently inhibited proliferation of Chinese hamster ovary (CHO) cells engineered to express PCFT, but not RFC or FRá (R2/PCFT4) (IC50s of 6 and 1.5 nM, respectively), or FRá without PCFT or RFC (RT16) (IC50s of 4.8 and 5.4 nM). AGF278 and AGF283 also inhibited growth of IGROV1 (IC50s of 1.5 and 11 nM, respectively) and SKOV3 (IC50s of 37.8 and 30.2 nM, respectively) ovarian cancer cells. We measured [3H]methotrexate uptake in R2/PCFT4 CHO cells in the presence of AGF278 and AGF283; AGF278 and AGF283 potently inhibited PCFT transport with increased binding over AGF117 and AGF150, respectively, as reflected in Ki values. Analogous to AGF117 and AGF150, glycinamide ribonucleotide (GAR) formyltransferase (GARFTase), the first folate-dependent enzyme in de novo purine biosynthesis, was implicated as the cellular target for AGF278 and AGF283 as adenosine (10 ìM) and 5-aminoimidazole-4-carboxamide (320 ìM) protected IGROV1 cells from growth inhibition. GARFTase inhibition by AGF278 and AGF283 was confirmed by an in situ GARFTase assay which measures incorporation of [14C]glycine into formyl GAR, the GARFTase product, with potencies similar to those of the parent molecules. Preliminary in vivo studies with AGF278 using SKOV3 tumor xenografts in SCID mice established antitumor efficacy. Our results suggest that novel fluorinated 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates may offer significant promise for treating ovarian cancer, reflecting their selective cellular uptake by PCFT and FRá and potent inhibition of de novo purine biosynthesis. Additional utility of our fluorine-substituted analogs lies in their potential for positron emission tomography imaging of PCFT-expressing tumors. Citation Format: Mike R. Wilson, Manasa P. Ravindraa, Adrianne Wallace-Povirk, Lisa Polin, Zhanjun Hou, Aleem Gangjee, Larry H. Matherly. Targeting ovarian cancer with novel 6-substituted pyrrolo [2,3-d] pyrimidine fluorinated antifolates via cellular uptake by folate receptor á and the proton-coupled folate transporter. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4791.

Improved mesophase stability of benzoxazole derivatives via dipole moment modification

By modifying the molecular dipole moments with lateral monofluorine substituent, improved mesophase stabilities were obtained for novel benzoxazole derivatives, 2-(4ʹ-alkoxy-3-fluorobiphenyl-4-yl)-benzoxazole liquid crystals (coded as nPPF(3)Bx). The series of nPPF(3)Bx with lateral monofluorine substituent ortho to benzoxazole group have larger calculated dipole moments by about 2 D than the corresponding fluorine-substituted analogs (compounds I) with lateral monofluorine ortho to alkoxy group; it is interesting to note that they show lower melting and clearing points but better mesophase stability with wider mesophase ranges for the molecules with both polar (NO2, Cl) and nonpolar (CH3, H) terminal groups. Meanwhile, compounds nPPF(3)Bx show greater red-shifted photoluminescence emissions than compounds I, which suggest that π–π interaction between molecules is reinforced by the enhanced dipole–dipole interaction caused by increased dipole moments. These results suggest that modification of the molecular dipole moment is an effective method to improve the mesophase stability of the classical mesogenic compounds.

Preparation and properties of lateral monofluoro-substituted benzoxazole-based mesogenic compounds

A series of 2-(3ʹ-fluoro-4ʹ-alkoxy-1,1ʹ-biphenyl-4-yl)-benzoxazole liquid crystals (coded as nPF(3)PBx) were prepared, where a lateral fluorine substituent, as well as methyl, chlorine and nitro terminal groups, was introduced into the molecules to investigate the effects of different polar substituents on the liquid crystal properties. The mesomorphic and photophysical properties were investigated. The results show that compounds nPF(3)PBx have enantiotropic mesophases; meanwhile, they exhibit UV–vis absorption bands with maxima at 323–326 nm and photoluminescence emission peaks at 389–395 nm, respectively. It is noted that nPF(3)PBx with terminal polar groups or electron-withdrawing groups (NO2, Cl) display higher clearing temperatures and wider mesophase range than those of the corresponding homologues with terminal non-polar groups or electron-donating groups (CH3, H). Meanwhile, compared with two lateral fluorine-substituted analogues containing 3,5-difluorophenyl unit, lateral monofluoro-substituted nPF(3)PBx display enhanced mesophase range both in heating and cooling except for terminal methyl-substituted compounds, as well as show obvious red-shifted UV–vis absorption bands and photoluminescence emission, which are attributed to the enhanced dipole–dipole interaction caused by increased dipole moment.

Synthesis of isocryptolepine analogues and their structure–activity relationship studies as antiplasmodial and antiproliferative agents

Novel isocryptolepine analogues have been conveniently synthesized and evaluated for antimalarial and antiproliferative activities. We have found 3-fluoro-8-bromo-isocryptolepine (1n) to have the highest activities against chloroquine-resistant K1, chloroquine-sensitive 3D7, and chloroquine- and mefloquine-resistant SKF58 and SRIV35 strains. Several fluorine-substituted analogues (1b, 1n, and 1q) also showed excellent selectivities while maintaining good to excellent activities against all four Plasmodium falciparum strains. Additionally, antiproliferative properties of isocryptolepine derivatives against HepG2, HuCCA-1, MOLT-3 and A549 cancer cell lines are reported for the first time in this study. 2-Chloroisocryptolepine (1c) and benzo-fused-2-chloroisocryptolepine (1i) showed significant bioactivities whereas several novel fluorinated compounds and 2-chloro-8-bromoisocryptolepine (1f) displayed excellent selectivities.

A Straightforward Synthesis of Chlorine-Bearing Donor-Acceptor Alternating Copolymers with Deep Frontier Orbital Levels

Donor–acceptor alternating copolymers with chlorine atoms on the backbone are synthesized via a straightforward Stille polycondensation. Thiophene and chlorine-substituted 2,3-diphenylquinoxaline are chosen as the donor and acceptor moieties, respectively. Compared with the corresponding non-substituted and fluorine-substituted analogues, which are also synthesized for systematical studies, the chlorine-bearing copolymer exhibits the deepest lowest unoccupied molecular orbital (LUMO). The highest occupied molecular orbital (HOMO) level of the chlorine-bearing copolymer can be modified by applying different donor moieties. Additionally, these chlorine-bearing copolymers show low self-absorption and large Stokes Shift.

Aromatic radiofluorination and biological evaluation of 2-aryl-6-[ 18F]fluorobenzothiazoles as a potential positron emission tomography imaging probe for β-amyloid plaques

To develop agents for radionuclide imaging Aβ plaques in vivo, we prepared three fluorine-substituted analogs of arylbenzothiazole class; compound 2 has a high affinity for Aβ ( K i = 5.5 nM) and the specific binding to Aβ in fluorescent staining. In preparation for the synthesis of these arylbenzothiazole analogs in radiolabeled form as an Aβ plaques-specific positron emission tomography (PET) imaging probe, we investigated synthetic route suitable for its labeling with the short-lived PET radionuclide fluorine-18 ( t 1/2 = 110 min) and diaryliodonium tosylate precursors ( 12, 13a– e and 14). 2-Aryl-6-[ 18F]fluorobenzothiazoles ([ 18F] 1– 3) were synthesized in efficiently short reaction times (40–60 min) with high radiochemical yields (19–40%), purities (>95%) and specific activities (85–118 GBq/μmol). Tissue distribution studies showed that high radioactivity of [ 18F] 2 accumulated in the brain with rapid clearance in healthy mice. Radioactive metabolites were analyzed in brain samples of mice and corresponded to 81% of parent remained by 30 min after a tail-vein injection. These results suggest that [ 18F] 2 is a promising probe for evaluation of Aβ plaques imaging in brain using PET.

Epoxide Opening with Tetrabutylammonium Fluoride (TBAF)

Positron emission tomography (PET) has been used to assess the fundamental and neurochemical parameters in normal and diseased human organisms. Measuring these parameters with PET requires the preparation of specific molecular imaging probes labeled with positron-emitting radioisotopes. Labeling pharmaceuticals with [F]fluorine often enables the fluorine-substituted analogue to be used to trace biochemical processes while maintaining favorable interaction with the target. Thus, a rapid and effective method for the introduction of F is a great concern in organofluorine and radiopharmaceutical chemistry. The typical method for introduction of a fluorine atom in an aliphatic molecule is the nucleophilic substitution of the corresponding sulfonates or halides by a fluoride ion. For example, the reaction of 2-(3-methanesulfonyloxypropoxy)naphthalene with CsF in t-BuOH gave 2-(3-fluoropropoxy)naphthalene in 92% yield along with the corresponding ether. Epoxide opening with a fluoride ion has been widely used in the preparation of fluorohydrins, which were often found in a certain bioactive molecules such as steroids, amino acids, carbohydrates, and prostaglandins. Anhydrous hydrogen fluoride is a good reagent for cleavage of the epoxide ring, but it is not easy to handle due to its toxicity and corrosiveness. To avoid this problem, some reagents have been developed; HF-amine complex, potassium hydrogen difluoride, silicon tetrafluoride, tetrabutylammonium dihydrogen trifluoride, and so on. Although these reagents gave successful results to some extent, most cases require heating at high temperature for a long period. In consequences, byproducts were often resulted from elimination, rearrangements or polymerization. Metal fluoride[F] or tetrabutylammonium fluoride[F] (TBAF) is a good source of the fluorinating agent to prepare radiopharmaceuticals containing F, but they were rarely used in the epoxide ring opening reaction. In this report, we examined epoxide opening reactions with metal fluoride or TBAF for introducing [F]fluorine to fluorohydrins.

Analyses of carbohydrate binding property of lectin-chaperone calreticulin

Calreticulin (CRT) is a soluble molecular chaperone of the endoplasmic reticulum. It is a lectin that promotes the folding of proteins carrying N-linked glycans. Recent investigations have revealed that glucosylated high-mannose-type glycans are employed as key elements in this process. Here, we performed quantitative analyses of the interaction of CRT with various disaccharides, including fluorine-substituted analogues using a quartz-crystal microbalance (QCM). These experiments revealed the weak affinity of 2- and 3-fluoroglucose derivatives. On the other hand, 6-fluoroglucose derivatives exhibited a significant affinity, indicating that the role of 6-position of OH is less significant for binding to CRT. We also characterized binding epitope of the Glcα1-3ManαMe to CRT by saturation transfer difference (STD) NMR spectroscopy. It is proposed that 2-, 3-, and 4-positions of Glc and 3-, 4-, and 6-positions of Man are in close contact with CRT binding pocket, while 6-position of Glc and 2-position of Man are not. These finding are in excellent agreement with our QCM experiment.

Methoxy- and Fluorine-Substituted Analogs of O-1302: Synthesis and in Vitro Binding Affinity for the CB1 Cannabinoid Receptor

Methoxy and fluorine analogs substituted on the terminal carbon of the pentyl chain of N-(piperidinyl)-1-(2,4-dichlorophenyl)-4-methyl-5-(4-pentylphenyl)-1H-pyrazole-3-carboxamide (O-1302) were synthesized in a multi-step process from 5-phenyl-1-pentanol, which was based on the 1,5-diarylpyrazole core template of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) through condensation of the respective amine with pyrazole carboxylic acid, in order to develop tracers for medical imaging. Their potency for inhibiting the binding of the CB1 antagonist [(3)H]SR141716 was evaluated with the aim of developing positron emission tomography (PET) ligands for the cerebral cannabinoid CB1 receptor. These analogs bearing a piperidinyl carboxamide at the C(3) of the pyrazole ring exhibited affinities comparable to those of the CB1 reference antagonist SR141716, which warrants further investigation using the radiolabeled form for biological imaging studies. A morpholine ring substituted at the C(3) of the pyrazole ring resulted in a reduction of the CB1 affinity.

Phenotype Analysis of Human Cytochrome P450 2C9 Polymorphism Using a Panel of Fluorine-Substituted Benzo[h]quinolines as Inhibitors of Tolbutamide Hydroxylation

To investigate the inhibitory effect of aza-polycyclic aromatic compounds on cytochrome P450 (CYP) 2C9 activity and analyze the fluorine-substitution effects on the CYP2C9 inhibition, benzo[h]quinoline (BhQ) and its fluorinated derivatives, 3-F-, 5-F-, 6-F-, 9-F-, 10-F-, 3,6-diF-, 5,6-diF-, 7,10-diF-BhQ, were subjected to analysis of their inhibitory effects on recombinant human CYP2C9.1-catalyzed tolbutamide hydroxylation. Although the inhibitory activity of BhQ itself on tolbutamide hydroxylation was not very strong (IC50 = 157 μ M), the inhibitory activities of BhQ derivatives on tolbutamide hydroxylation varied with the substituted fluorine positions. Their inhibitory activities decreased in the following order; (BhQ) > 7,10-diF ≥ 3,6-diF, 9-F ≥ 10-F > 6-F ≥ 5-F, 3-F ≥ 5,6-diF-BhQ. Moreover, the fluorine-substitution effect on the inhibition of tolbutamide hydroxylation catalyzed by wild-type CYP2C9 (CYP2C9.1) was different from the effects on the hydroxylation catalyzed by its polymorphic isozymes CYP2C9.2 and CYP2C9.3. The inhibitory activities of BhQs on tolbutamide hydroxylation by CYP2C9.2 decreased in the following order; 5-F ≥ 10-F, 9-F ≥ (BhQ) ≥ 7,10-diF > 6-F ≥ 5,6-diF, 3,6-diF > 3-F-BhQ, and those on the hydroxylation by CYP2C9.3 decreased in the follwing order; 7,10-diF, 10-F, (BhQ) ≥ 9-F, 5-F > 3-F ≥ 5,6-diF, 6-F, 3,6-diF-BhQ. The results thus showed that the position-specific substitution by fluorine atom(s) altered the CYP2C9 inhibition by BhQ derivatives in different manners depending on the polymorphic isozymes involved. These results suggest that inhibitory profiles obtained with fluorine-substituted analogs of the key inhibitor molecule may be useful as a new tool for phenotyping the polymorphic CYP isoforms.

Madelung−Buckingham Model as Applied to the Prediction of Voltage, Crystal Volume Changes, and Ordering Phenomena in Spinel-Type Cathodes for Lithium Batteries

Using a Madelung-Buckingham model, we study Li(x)()Mn(2)O(4) and its fluorine-substituted analogue to compute their voltages, lattice volume changes, and ordering phenomena during charge/discharge. The interactions included are the long-range Coulombic, short-range electron-electron repulsion, and the van der Waals. The voltage of the fluorine-substituted spinel is found to be slightly less than that of the unsubstituted. However, the former undergoes a greater crystal volume change than the latter during intercalation and de-intercalation. Investigations of lithium sublattice ordering in this system indicates that during intercalation lithium starts filling exclusively into one sublattice until x = 0.5, and only from x = 0.5 the other sublattice is filled up to x = 1. The models are compared with quantum ab initio and experimental results.

Fluorine mineralisation from burning coal spoil-heaps in the Russian Urals

Anhydrous iron, aluminum and fluorine-rich paralavas were found in the burned spoil-heaps of the Chelyabinsk coal basin, Russia. The rocks contain tridymite, anorthite, ferroan fluorine-bearing cordierite, fluorine-bearing mullite, periclase, fluorapatite, micas of the F-biotite–F-phlogopite series, fluortopaz, fluorite, and sellaite. The fluorine-rich minerals formed as a result of local thermal reactions of sedimentary carbonates and silicates with gaseous fluorine. During coal combustion fluorine concentrates in the annealed ankeritic marls where the increase of F is hundreds of times over its concentration in the initial sedimentary rocks. The formation of MgF2 and CaF2 promotes local melting at relatively low temperatures (T < 1000 °C) with the residuum consisting of two immiscible liquids. One crystallises as the fluorides, the other as fluorine-substituted analogues of the hydrosilicates, which under the extremely dry conditions, produce minerals containing extremely high F-contents.

Fluorine-substituted ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma): potential imaging agents for metastatic tumors.

The peroxisome proliferator-activated receptor gamma (PPARgamma), a primary regulator of lipid metabolism, is present in many tumor cell lines and animal tumor systems and, in some cases, can mediate effective antitumor therapy with potent synthetic ligands. In an approach to image tumors with positron-emission tomography (PET) based on their content of PPARgamma, we have synthesized two fluorine-substituted analogues of a high affinity ligand from the phenylpropanoic acid class. The analogue having the highest affinity for PPARgamma was labeled with the positron-emitting radionuclide fluorine-18. In tissue distribution studies in normal rats and in SCID mice bearing human breast tumor xenografts, this compound did not show evidence of receptor-mediated uptake. The prospects for using PPARgamma as a target for imaging tumors may be limited by the low receptor concentrations in tumors and by the pharmacokinetic behavior of this class of ligands, which appears to be more favorable for therapy than for imaging.

Effect of Fluorine Substitution on the Interaction of Lipophilic Ions with the Plasma Membrane of Mammalian Cells

The effects of the anionic tungsten carbonyl complex [W(CO) 5SC 6H 5] − and its fluorinated analog [W(CO) 5SC 6F 5] − on the electrical properties of the plasma membrane of mouse myeloma cells were studied by the single-cell electrorotation technique. At micromolar concentrations, both compounds gave rise to an additional antifield peak in the rotational spectra of cells, indicating that the plasma membrane displayed a strong dielectric dispersion. This means that both tungsten derivatives act as lipophilic ions that are able to introduce large amounts of mobile charges into the plasma membrane. The analysis of the rotational spectra allowed the evaluation not only of the passive electric properties of the plasma membrane and cytoplasm, but also of the ion transport parameters, such as the surface concentration, partition coefficient, and translocation rate constant of the lipophilic anions dissolved in the plasma membrane. Comparison of the membrane transport parameters for the two anions showed that the fluorine-substituted analog was more lipophilic, but its translocation across the plasma membrane was slower by at least one order of magnitude than that of the parent hydrogenated anion.

Preparation of 5-[ 131I]Iodo- and 5-[ 211At]Astato-1- (2-Deoxy-2-Fluoro-β- d-Arabinofuranosyl)Uracil by a Halodestannylation Reaction

To circumvent the in vivo instability of 5-iodo-2′-deoxyuridine (IUdR), a 2′-fluorine-substituted analogue, 5-iodo-1-(2-deoxy-2-fluoro-β- d-arabinofuranosyl)uracil (FIAU) recently has been introduced. To facilitate the preparation of radioiodinated FIAU as well as its astatinated analogue, a tin precursor, 5-trimethylstannyl-1-(2-deoxy-2-fluoro-β- d-arabinofuranosyl)uracil (FTAU) was synthesized. Both [ 125/131I]FIAU and 5-[ 211At]astato-1-(2-deoxy-2-fluoro-β- d-arabinofuranosyl)uracil (FAAU) were prepared from FTAU in more than 85% radiochemical yield under mild conditions. The in vitro serum stability of both fluorine-substituted derivatives was higher than that of the corresponding unsubstituted parents. The enhanced stability of fluorinated derivatives was even more apparent in whole blood. The uptake of [ 125I]FIAU in D-247 MG human glioma cells in vitro was 20-fold higher than that of [ 125I]IUdR over an activity concentration range of 5–100 kBq/mL; the uptake of FAAU was not significantly different from that of 5-[ 211At]astato-2′-deoxyuridine (AUdR). Accumulation of radioiodine in mouse thyroid in vivo with [ 131I]FIAU was fivefold lower than [ 125I]IUdR, indicating that the former was less susceptible to deiodination. The tissue uptake of FAAU was similar to that reported for AUdR.

H-19F NOE difference spectroscopy as a tool for structural assignment of positional isomers in fluorine-substituted analogues of FPL 64176

Two difluorinated analogues of FPL 64176 (methyl 4-(2-benzylbenzoyl)-2,5-dimethylpyrrole-3-carboxylate) have been synthesized in three steps from 6-fluorophthalide and methyl 2,5-dimethylpyrrole-3-carboxylate. Significant overlap of signals was observed in the aromatic regions of the 1H NMR spectra of these compounds. Using 1H- 1H and 1H- 19F NOE difference spectroscopy it was possible to identify and assign all aromatic resonances and, based on the NOEs observed, differentiate between the positional isomers and definitely assign the structure of each.